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N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 is overexpressed in cancer and promotes a pro-migratory and pro-metastatic phenotype

Oncogene volume 33, pages 5274–5287 (2014)Cite this article

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Abstract

N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 (NAALADL2) is a member of the glutamate carboxypeptidase II family, best characterized by prostate-specific membrane antigen (PSMA/NAALAD1). Using immunohistochemistry (IHC), we have shown overexpression of NAALADL2 in colon and prostate tumours when compared with benign tissue. In prostate cancer, NAALADL2 expression was associated with stage and Grade, as well as circulating mRNA levels of the NAALADL2 gene. Overexpression of NAALADL2 was shown to predict poor survival following radical prostatectomy. In contrast to PSMA/NAALAD1, NAALADL2 was localized at the basal cell surface where it promotes adhesion to extracellular matrix proteins. Using stable knockdown and overexpression cell lines, we have demonstrated NAALADL2-dependent changes in cell migration, invasion and colony-forming potential. Expression arrays of the knockdown and overexpression cell lines have identified nine genes that co-expressed with NAALADL2, which included membrane proteins and genes known to be androgen regulated, including the prostate cancer biomarkers AGR2 and SPON2. Androgen regulation was confirmed in a number of these genes, although NAALADL2 itself was not found to be androgen regulated. NAALADL2 was also found to regulate levels of Ser133 phosphorylated C-AMP-binding protein (CREB), a master regulator of a number of cellular processes involved in cancer development and progression. In combination, these data suggest that changes in expression of NAALADL2 can impact upon a number of pro-oncogenic pathways and processes, making it a useful biomarker for both diagnosis and prognosis.

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Acknowledgements

We would like to acknowledge the support of The University of Cambridge, Cancer Research UK, National Medical Research Council, Singapore and Hutchison Whampoa Limited; the National Institute of Health Research, which funds the Cambridge Bio-medical Research Centre, Cambridge, UK; the National Cancer Research Prostate Cancer: mechanisms of Progression and Treatment (PROMPT) collaborative (grant code G0500966/75466), which has funded tissue collections in Cambridge. We would like to thank Prostate Cancer UK for funding a proportion of this work. We are very grateful to the Cancer Research UK Cambridge Institute Genomics Core Facility, Histopathology and ISH Facility, and Bioinformatics and Statistics Core Facility for their assistance with the work in this manuscript. We would also like to thank Erik Sahai (Cancer Research UK London Research Institute) and Ian Mills (Centre for Molecular Medicine Norway) for their helpful discussions in preparing this manuscript.

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Author notes

  1. H C Whitaker and L L Shiong: These authors contributed equally to this work.

Authors and Affiliations

  1. Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    H C Whitaker, L L Shiong, J D Kay, B Thomas, A Ramos-Montoya, C Massie & D E Neal

  2. Cancer Research UK Biomarker Initiative, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    H C Whitaker

  3. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden

    H Grönberg & F Wiklund

  4. Department of Histopathology and ISH Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    A Y Warren & J L Miller

  5. Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    A Y Warren & J L Miller

  6. Department of Pathology, Karolinska Institute, Stockholm, Sweden

    A Seipel, P Wiklund & L Egevad

  7. Bioinformatics Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, UK

    S Menon & S L Vowler

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Whitaker, H., Shiong, L., Kay, J. et al. N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 is overexpressed in cancer and promotes a pro-migratory and pro-metastatic phenotype. Oncogene 33, 5274–5287 (2014). https://doi.org/10.1038/onc.2013.464

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